The University of Louisville Molecular Targets Center of Biomedical Research Excellence application (MTCOBRE) is focused on the identification of novel molecular targets for cancer therapy using the techniques of modern structural biology. The two major objectives of this proposal are to ensure the success of junior investigators who are members of the Molecular Targets Program at the University of Louisville and to discover new approaches to the therapy of cancer. The Specific Aims of the Molecular Targets COBRE application are to: 1. Foster successful independent research careers for each of the five principal investigators leading to independent R01 grants. 2. Further build our existing core facilities which will enhance the research capability of the five principal investigators and the other members of the program. 3. Continue to develop our Molecular Targets Program as a cohesive research program which will promote collaborative research projects and increase funding opportunities. 4. Develop an internationally and nationally recognized program which will attract the very best graduate students, postdoctoral fellows and additional faculty. 5. Most importantly, make discoveries leading to new and more effective treatments for patients with cancer. The five related projects of this MT-COBRE application will address a broad spectrum of molecular targets. The specific problems being investigated are: 1) Characterization and manipulation of an inducible isoform of 6-phosphofructo-2-kinase (iPFK-2), a major controller of glucose metabolism in malignant cells. 2) Development and testing of small molecular antagonists of monocyte/macrophage migration inhibitory factor (MIF) recently found to play an important role in carcinogenesis. 3) Elucidation of the signaling mechanisms involved in the activation-dependent lipid signaling enzyme, sphingosine kinase, and its product, sphingosine-l-phosphate, in control of cell proliferation, survival and migration. 4) Use of triplex forming oligonucleotides to target Bleomycin to the Her2/neu gene. 5) A crystallographer/biologist is being recruited to study molecular interactions important in the TRAF signaling pathway. The overarching theme of this program is the use of structural biology to develop novel strategies for therapy of neoplastic disease. We believe that these five projects, along with those of the other members of the program, represent a coherent approach to the application of modern structural biology to translational cancer research.